EPO, in both the endogenous and recombinant form, has a single polypeptide chain backbone composed of 165 amino acids (5). rHuEPO forms a bundle of 4 a-helices that are folded into a compact globular structure (6,7). Separate regions of the molecule contain the two EPO receptor-binding (EPOR) sites (6,8) of high (site 1: 1 nM) and low (site 2: 4 pM) affinity (9,10). Receptor activation occurs when one EPO molecule homodimerizes two EPOR molecules (6,11).
EPO undergoes post-translational glycosylation at three specific asparagine residues (Asn24, Asn38, and Asn83) and one serine residue (Ser126) (12,13) (Fig. 1). In mammalian cells, the carbohydrate chains are typically of the complex type and contribute to approx 40% of the mass of the hormone (14). The polypeptide backbone of the human EPO molecule has an invariant sequence and structure; however, the carbohydrate chains exhibit microheterogeneity in terms of composition and structure (15-17). A negatively charged sialic acid molecule typically caps the end of each carbohydrate chain branch. As a consequence, the variable nature of the sialic acid content results in EPO isoforms with differences in charge.
The ^-linked carbohydrates are important for retention of in vivo but not in vitro biologic activity (16,18), and their sialic acid residues ensure, and promote, the molecule's survival in the circulation (19).
Several rEPO molecules are used clinically, including epoetin alfa and epoetin beta. Epoetin alfa (marketed as Epogen®, Procrit®, Eprex®, and Erypo®) is available in most of the developed world, including the United States, Europe, Canada, Australia, and Asia. Epoetin beta (NeoRecormon®) is available in Europe and Japan. Both of these types of rHuEPO are produced in Chinese hamster ovary (CHO) cultures. No important differences in their clinical efficacy are apparent, and they are generally used interchangeably (20). A novel glycosylation analog of EPO, darbepoetin alfa (Aranesp®) has the same safety profile and performs the same function as rHuEPO; however, it has a threefold increased serum half-life and increased in vivo potency, allowing for more flexible modes of administration, including extended dosing. Other rHuEPO moieties such as epoetin omega, are also marketed in Eastern Europe, Mexico, and South America.
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WHAT IT IS A three-phase plan that has been likened to the low-carbohydrate Atkins program because during the first two weeks, South Beach eliminates most carbs, including bread, pasta, potatoes, fruit and most dairy products. In PHASE 2, healthy carbs, including most fruits, whole grains and dairy products are gradually reintroduced, but processed carbs such as bagels, cookies, cornflakes, regular pasta and rice cakes remain on the list of foods to avoid or eat rarely.